The cornea is a transparent, avascular tissue having a diameter of about 1 cm and a thickness of about 1 mm. Transparency of the cornea affects visual functions greatly and various physiological and biochemical phenomena in the cornea function mainly with an object of maintenance of transparency of the cornea.
Corneal epithelial defects caused by various diseases such as corneal ulcer, corneal erosion, keratitis and dry eye heals spontaneously unless mixed infection intercurrently occurs. However, if the healing is delayed or does not occur due to some causes and the corneal defects become persistent, the normal construction of the epithelium is badly affected, and further even the structure and function of corneal stroma and endothelium are damaged. The principle of the conventional therapeutic methods is merely passive, i.e., the surface of the cornea is protected from outside stimulation whereby the epithelium is spontaneously extended to re-cover the defected area. Recent progress of cell biology has revealed factors participating in proliferation, migration, attachment, spreading of cells, etc. and it was reported that compounds which enhance the migration of corneal epithelium play an important role in healing the corneal epithelial defects (Jpn. J. Clin. Ophthalmol., 46, 738-743 (1992); and Jpn. J. Ophthalm. Surg., 5, 719-727 (1992)).
FGLM is a tetrapeptide at the C-terminal of Substance P which is disclosed in U.S. Pat. No. 3,862,114 and the patent describes that it has an hypotensive action. Substance P is a polypeptide consisting of eleven amino acids which show actions such as vasodilation, smooth muscle contraction, promotion of salivary gland secretion and diuresis. With regard to Substance P, various studies were conducted in an ophthalmic field. For example, improvement in aberrant conjunctival goblet cell secretion in ophthalmic diseases was disclosed (WO95/13087) and sequential charges of Substance P in inflammation such as keratitis was reported (J. Jpn. Ophthalmol. Soc., 91, 982-987 (1987); ibid., 92, 448-452 (1988)). However, there has been no report on FGLM, which is its partial peptide, in an ophthalmic field.
On the other hand, an insulin-like growth factor is one of the growth factors controlling the growth of normal human cells such as epidermal growth factor, fibroblast growth factor, platelet-derived growth factor and transforming growth factor, and there are IGF-I and an insulin-like growth factor II (hereinafter, referred to as IGF-II) therein. Recently, it was reported that IGF-I stimulates thyroid cell proliferation (J. Biol. Chem., 264, 18485-18488 (1989)), that IGF-II regulates muscle growth and differentiation (Hum. Mol. Genet., 3, 1117-1121 (1994)), etc. In an ophthalmic field, also, it was disclosed that IGF-I, IGF-II and functional derivatives thereof promote the survival of retinal neurons (cf. Japanese Laid-Open Patent Publication Hei-07/500,839), that IGF-II is effective for therapy of every wound of various areas including the wound upon corneal transplantation (Japanese Laid-Open Patent Publication Sho-63/233,925) and that ocular tissues such as cornea provided to transplantation can be preserved at low temperature in a fresh state of the tissues by using a solution containing the above-mentioned growth factor (Japanese Laid-Open Patent Publications Hei-05/025,001 and Hei-06/048,901). It was also disclosed that, in general, gel compositions containing the growth factor are effective for wound healing in anterior segments etc. (Japanese Laid-Open Patent Publication Hei-02/000,112). However, the growth factors which are specifically disclosed in those patent publications are epidermal growth factors only and there is no description on the effect of IGF-I.
IGF-II has been known to be useful for a therapy of wound upon corneal transplantation etc. as mentioned above. However, with regard to IGF-I, there is only a report that it does not affect corneal epithelial wound healing (Connect. Tissue, 27, 65 (1995)).
It was reported that Substance P itself does not affect the corneal epithelial wound healing but it promotes the corneal epithelial wound healing when it coexists with epidermal growth factor out of growth factor (Prog. Med., 13, 2626-2627 (1993)) or IGF-I (Connect. Tissue, 27, 65 (1995)). However, it has not been revealed that which site of Substance P is an activity-exhibiting site.
As mentioned above, it has been a very interesting subject to find a minimum activity-exhibiting site of Substance P and to study actions of the compound in such a minimum unit in an ophthalmic field, particularly to study the action on corneal disorders.